CHCHD4 Oxidoreductase Activity: A Comprehensive Analysis of the Molecular, Functional, and Structural Properties of Its Redox-Regulated Substrates

Human CHCHD4 is the prototype of the proteins carrying a coiled-coil-helix-coiled-coil-helix motif that is stabilized by two disulfide bonds. Using its CPC sequence motif, CHCHD4 plays a key role in mitochondrial metabolism, cell survival, and response to stress conditions controlling the mitochondrial import of diversified protein substrates that are specifically recognized through an interplay between covalent and non-covalent interactions. In the present review, we provide an updated and comprehensive analysis of CHCHD4 substrates controlled by its redox activities. A particular emphasis has been given to the molecular and structural aspects of these partnerships. The literature survey has been integrated with the mining of structural databases reporting either experimental (Protein Data Bank) or structures predicted by AlphaFold, which provide protein three-dimensional models using machine learning-based approaches. In providing an updated view of the thirty-four CHCHD4 substrates that have been experimentally validated, our analyses highlight the notion that this protein can operate on a variety of structurally diversified substrates. Although in most cases, CHCHD4 plays a crucial role in the formation of disulfide bridges that stabilize in helix-coil-helix motifs of its substrates, significant variations on this common theme are observed, especially for substrates that have been more recently identified.